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Case summary A 5‐year‐old neutered male domestic medium‐hair cat was referred to the internal medicine department with upper respiratory signs and limb pain. Computed tomography (CT) revealed diffuse osteosclerosis, showing severe osseous thickening of the nasal turbinates and near‐occlusion of the nasal passages. No new or healed fractures were observed. Additional diagnostic tests revealed no infectious or neoplastic causes. The cat was treated supportively for pain and nasal inflammation. One year after the diagnosis, the cat was described as having an acceptable quality of life at home, despite ongoing clinical signs of nasal congestion. Relevance and novel information Chronic upper airway congestion is a common presenting complaint in feline patients. This report describes the imaging findings in a cat in which upper airway signs were due in part to systemic bone pathology. Previous reports suggest that the most common causes of chronic nasal congestion are acquired conditions with poor prognosis, such as lymphoplasmacytic rhinitis, neoplasia, or fungal infection. Diseases that cause diffuse osteosclerosis in cats are poorly understood. This report describes a case of diffuse osteosclerosis in a young cat with no other known comorbidities. The clinical picture is similar to descriptions of an osteosclerotic bone disorder in humans commonly referred to as autosomal dominant osteopetrosis type 1. Since no targeted treatments are available to reverse the osseous changes, the patient was treated supportively with pain management and corticosteroids. Recent developments in our understanding and treatment of similar human diseases may guide future advances in veterinary medicine. Chronic upper airway congestion is a common presenting complaint in feline patients. This report describes the imaging findings in a cat in which upper airway signs were due in part to a systemic bone pathology that was also leading to decreased mobility. Computed tomography (CT) revealed diffuse osteosclerosis. The clinical picture is similar to descriptions of inherited osteosclerotic bone disorders in humans associated with increased bone mineral density.

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated \"fat-free\" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

This study aimed to investigate the cone-beam computed tomography (CBCT) follow-up of adult patients with asymptomatic, incidentally encountered idiopathic osteosclerosis (IO) to demonstrate its natural course. Retrospectively, 37 patients (mean age, 40.5 years; 19 females and 18 males) with mandibular IO were included, based upon clinico-radiological features. Inclusion criteria were a baseline and at least one follow-up CBCT scan after 12 months or later, no periapical inflammatory lesion, and no previous endodontic or surgical treatment in the respective dentate region. Changes of maximum axial and cranio-caudal diameter and morphology (tooth relationship, lesional shape, radiodensity, endosteum and mandibular canal relationship, root resorption) were evaluated in 45 lesions and descriptively analyzed. The interreader agreement was calculated for diameter and morphological evaluation by intraclass correlation coefficient (ICC) and weighted κ statistics, respectively. The results showed that none of the lesions changed in diameter nor in morphology within the respective follow-up (mean, 19.0 months, maximum 96.0 months). Overall, there was high interreader agreement (up to ICC = 0.854, and weighted κ = 1). In conclusion, on CBCT, IO morphometrics and morphology may naturally remain unchanged in asymptomatic adults, even after up to eight years of follow-up. Consequently, once the diagnosis of IO has been established, CBCT follow-up might not be justified to prevent imaging overuse, which is associated with an excess of ionizing radiation exposure.

WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2-mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were β-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFβ/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFβ/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFβ-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFβ–YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

To study the effects of low-density lipoprotein receptor-related protein 5 ( LRP5 ) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (β-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1–4: 1.877 g/cm 2 , Z-score: 5.8; total hip: 1.705 g/cm 2 , Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and β-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.

Idiopathic osteosclerosis (IO) are focal radiopacities of unknown etiology observed in the jaws. These radiopacities are incidentally detected on dental panoramic radiographs taken for other reasons. In this study, we investigated the performance of a deep learning model in detecting IO using a small dataset of dental panoramic radiographs with varying contrasts and features. Two radiologists collected 175 IO-diagnosed dental panoramic radiographs from the dental school database. The dataset size is limited due to the rarity of IO, with its incidence in the Turkish population reported as 2.7% in studies. To overcome this limitation, data augmentation was performed by horizontally flipping the images, resulting in an augmented dataset of 350 panoramic radiographs. The images were annotated by two radiologists and divided into approximately 70% for training (245 radiographs), 15% for validation (53 radiographs), and 15% for testing (52 radiographs). The study employing the YOLOv5 deep learning model evaluated the results using precision, recall, F1-score, mAP (mean Average Precision), and average inference time score metrics. The training and testing processes were conducted on the Google Colab Pro virtual machine. The test process's performance criteria were obtained with a precision value of 0.981, a recall value of 0.929, an F1-score value of 0.954, and an average inference time of 25.4 ms. Although radiographs diagnosed with IO have a small dataset and exhibit different contrasts and features, it has been observed that the deep learning model provides high detection speed, accuracy, and localization results. The automatic identification of IO lesions using artificial intelligence algorithms, with high success rates, can contribute to the clinical workflow of dentists by preventing unnecessary biopsy procedure.

PurposeSystemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear.MethodsBMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis.ResultsOsteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031).ConclusionsOsteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

Raine syndrome is characterized by FGF23-mediated hypophosphatemic osteomalacia with osteosclerosis caused by mutations in the FAM20C gene. We report a case of a 72-year-old man who presented with rapid progressive spontaneous osteonecrosis of the knee (SONK). A full osteologic assessment including dual energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses revealed a high bone mass in the lumbar spine and hip (DXA T-score + 7.5 and + 4.7/+4.2) with increased bone microstructural parameters in the distal radius and tibia (BV/TV 127%, 140% of the age-matched mean, respectively), as well as a low bone turnover state. Phosphate levels were low due to renal phosphate wasting and high FGF23 levels (126.5 pg/ml, reference range 23.2–95.4 pg/ml). Using gene panel sequencing, we identified a novel FAM20C heterozygous missense mutation in combination with a homozygous duplication that potentially alters splicing. Taken together, this is the first case of mild Raine syndrome with spontaneous osteonecrosis of the knee, phosphate wasting, and a pronounced trabecular high bone mass phenotype.

Idiopathic osteosclerosis (IOS) and condensing osteitis (CO) represent radiopaque lesions often detected incidentally within the jaws, posing substantial diagnostic challenges due to their overlapping radiographic characteristics. The objective of this study was to assess the diagnostic efficacy of YOLOv8 and YOLOv11 deep learning algorithms in the identification of IOS and CO lesions on panoramic radiographs. A comprehensive collection of 1,000 panoramic images was retrospectively gathered and meticulously annotated utilizing a bounding box approach by two proficient oral and maxillofacial radiologists. All images were standardized to a resolution of 640 × 640 pixels and segregated into training (70%), validation (15%), and testing (15%) subsets. The performance of the models was evaluated based on metrics including accuracy, sensitivity, precision, F1 score, and the area under the receiver operating characteristic curve (AUC). YOLOv11 achieved notable precision scores of 98.8% for IOS and 97.1% for CO, alongside F1 scores of 96.8% and 95.6%, respectively. Conversely, YOLOv8 produced precision scores of 96.6% for IOS and 91.4% for CO, with F1 scores of 94% and 90%. These findings illustrate that AI-enhanced deep learning models possess the capability to accurately identify IOS and CO lesions, thereby presenting opportunities to improve diagnostic consistency, avert unnecessary invasive procedures, and facilitate more effective treatment planning within clinical practice.